scholarly journals Disruption of Steroid and Prolactin Receptor Patterning in the Mammary Gland Correlates with a Block in Lobuloalveolar Development

2002 ◽  
Vol 16 (12) ◽  
pp. 2675-2691 ◽  
Author(s):  
Sandra L. Grimm ◽  
Tiffany N. Seagroves ◽  
Elena B. Kabotyanski ◽  
Russell C. Hovey ◽  
Barbara K. Vonderhaar ◽  
...  
Keyword(s):  
Cell Fate ◽  
Binding Protein ◽  
Prolactin Receptor ◽  
Mammary Epithelium ◽  
Mammary Epithelial ◽  
Epidermal Differentiation ◽  
Bzip Transcription Factor ◽  
Mammary Tissue ◽  
Critical Determinant ◽  
Lobuloalveolar Development

Abstract Targeted deletion of the bZIP transcription factor, CCAAT/enhancer binding protein-β (C/EBPβ), was shown previously to result in aberrant ductal morphogenesis and decreased lobuloalveolar development, accompanied by an altered pattern of progesterone receptor (PR) expression. Here, similar changes in the level and pattern of prolactin receptor (PrlR) expression were observed while screening for differentially expressed genes in C/EBPβnull mice. PR patterning was also altered in PrlRnull mice, as well as in mammary tissue transplants from both PrlRnull and signal transducer and activator of transcription (Stat) 5a/b-deficient mice, with concomitant defects in hormone-induced proliferation. Down-regulation of PR and activation of Stat5 phosphorylation were seen after estrogen and progesterone treatment in both C/EBPβnull and wild-type mice, indicating that these signaling pathways were functional, despite the failure of steroid hormones to induce proliferation. IGF binding protein-5, IGF-II, and insulin receptor substrate-1 all displayed altered patterns and levels of expression in C/EBPβnull mice, suggestive of a change in the IGF signaling axis. In addition, small proline-rich protein (SPRR2A), a marker of epidermal differentiation, and keratin 6 were misexpressed in the mammary epithelium of C/EBPβnull mice. Together, these data suggest that C/EBPβ is a master regulator of mammary epithelial cell fate and that the correct spatial pattern of PR and PrlR expression is a critical determinant of hormone-regulated cell proliferation.

scholarly journals Hyperactive WNT/CTNNB1 signaling induces a competing cell proliferation and epidermal differentiation response in the mouse mammary epithelium

2021 ◽  
Author(s):  
Larissa Mourao ◽  
Amber L. Zeeman ◽  
Katrin E. Wiese ◽  
Anika Bongaarts ◽  
Lieve L. Oudejans ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Fate ◽  
De Novo ◽  
Mammary Epithelium ◽  
Mechanistic Explanation ◽  
Tumor Formation ◽  
Epidermal Differentiation ◽  
Cell Proliferation And Differentiation ◽  
Primary Mouse ◽  
Proliferation And Differentiation

In the past forty years, the WNT/CTNNB1 signaling pathway has emerged as a key player in mammary gland development and homeostasis. While also evidently involved in breast cancer, much unclarity continues to surround its precise role in mammary tumor formation and progression. This is largely due to the fact that the specific and direct effects of hyperactive WNT/CTNNB1 signaling on the mammary epithelium remain unknown. Here we use a primary mouse mammary organoid culture system to close this fundamental knowledge gap. We show that hyperactive WNT/CTNNB1 signaling induces competing cell proliferation and differentiation responses. While proliferation is dominant at lower levels of WNT/CTNNB1 signaling activity, higher levels cause reprogramming towards an epidermal cell fate. We show that this involves de novo activation of the epidermal differentiation cluster (EDC) locus and we identify master regulatory transcription factors that likely control the process. This is the first time that the molecular and cellular dose-response effects of WNT/CTNNB1 signaling in the mammary epithelium have been dissected in such detail. Our analyses reveal that the mammary epithelium is exquisitely sensitive to small changes in WNT/CTNNB1 signaling and offer a mechanistic explanation for the squamous differentiation that is observed in some WNT/CTNNB1 driven tumors.

scholarly journals cAMP Response Element Binding Protein 1 (CREB1) Promotes Monounsaturated Fatty Acid Synthesis and Triacylglycerol Accumulation in Goat Mammary Epithelial Cells

Animals ◽  
2020 ◽  
Vol 10 (10) ◽  
pp. 1871
Author(s):  
Dawei Yao ◽  
Chunlei Yang ◽  
Jing Ma ◽  
Lili Chen ◽  
Jun Luo ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Mammary Epithelial Cells ◽  
Binding Protein ◽  
Lipid Synthesis ◽  
Acid Synthesis ◽  
Camp Response Element Binding ◽  
Mammary Epithelial ◽  
Mammary Tissue ◽  
Camp Response Element ◽  
Element Binding Protein

cAMP response element binding protein 1 (CREB1) is a member of the leucine zipper transcription factor family of DNA binding proteins. Although studies in non-ruminants have demonstrated a crucial role of CREB1 in lipid synthesis in liver and adipose tissue, it is unknown if this transcription regulator exerts control of fatty acid synthesis in ruminant mammary cells. To address this question, we first defined the expression dynamics of CREB1 in mammary tissue during lactation. Analysis of CREB1 in mammary tissue revealed higher mRNA abundance in mammary tissue harvested at peak lactation. Overexpression of CREB1 markedly upregulated sterol regulatory element binding transcription factor 1 (SREBP1), fatty acid synthase (FASN), acetyl-coenzyme A carboxylase α (ACACA), elongase of very long chain fatty acids 6 (ELOVL6), lipoprotein lipase (LPL), fatty acid binding protein 3 (FABP3), lipin 1 (LPIN1) and diacylglycerol acyltransferase 1 (DGAT1), but had no effect on glycerol-3-phosphate acyltransferase, mitochondrial (GPAM) or 1-acylglycerol-3-phosphate O-acyltransferase 6 (AGPAT6). In addition, overexpressing CREB1 led to a significant increase in the concentration and desaturation index of C16:1 (palmitoleic acid) and C18:1 (oleic acid), along with increased concentration of triacylglycerol. Taken together, these results highlight an important role of CREB1 in regulating lipid synthesis in goat mammary epithelial cells. Thus, manipulation of CREB1 in vivo might be one approach to improve the quality of goat milk.

scholarly journals Regulation of Mammary Gland Branching Morphogenesis by EphA2 Receptor Tyrosine Kinase

2009 ◽  
Vol 20 (10) ◽  
pp. 2572-2581 ◽  
Author(s):  
David Vaught ◽  
Jin Chen ◽  
Dana M. Brantley-Sieders
Keyword(s):  
Mammary Gland ◽  
Mammary Gland Development ◽  
Mammary Epithelium ◽  
Branching Morphogenesis ◽  
Mammary Epithelial ◽  
Mammary Tissue ◽  
Wild Type ◽  
Epithelial Proliferation ◽  
Positive Role ◽  
Gland Development

Eph receptor tyrosine kinases, including EphA2, are expressed in the mammary gland. However, their role in mammary gland development remains poorly understood. Using EphA2-deficient animals, we demonstrate for the first time that EphA2 receptor function is required for mammary epithelial growth and branching morphogenesis. Loss of EphA2 decreased penetration of mammary epithelium into fat pad, reduced epithelial proliferation, and inhibited epithelial branching. These defects appear to be intrinsic to loss of EphA2 in epithelium, as transplantation of EphA2-deficient mammary tissue into wild-type recipient stroma recapitulated these defects. In addition, HGF-induced mammary epithelial branching morphogenesis was significantly reduced in EphA2-deficient cells relative to wild-type cells, which correlated with elevated basal RhoA activity. Moreover, inhibition of ROCK kinase activity in EphA2-deficient mammary epithelium rescued branching defects in primary three-dimensional cultures. These results suggest that EphA2 receptor acts as a positive regulator in mammary gland development, functioning downstream of HGF to regulate branching through inhibition of RhoA. Together, these data demonstrate a positive role for EphA2 during normal mammary epithelial proliferation and branching morphogenesis.

scholarly journals Mammary Epithelial Cells Are Not Able to Undergo Pregnancy-Dependent Differentiation in the Absence of the Helix-Loop-Helix Inhibitor Id2

2002 ◽  
Vol 16 (12) ◽  
pp. 2892-2901 ◽  
Author(s):  
Keiko Miyoshi ◽  
Barbara Meyer ◽  
Peter Gruss ◽  
Yongzhi Cui ◽  
Jean-Pierre Renou ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Mammary Epithelial Cells ◽  
Early Stage ◽  
Prolactin Receptor ◽  
Signal Transduction Pathway ◽  
Mammary Epithelium ◽  
Mammary Epithelial ◽  
Differentiation Markers ◽  
Helix Loop Helix ◽  
Alveolar Development

Abstract Mammary alveolar development during pregnancy is triggered by hormone signals. The prolactin receptor/Jak2/signal transducer and activator of transcription (Stat) 5 signal transduction pathway is the principal mediator of these cues and alveolar development is abrogated in its absence. The loss of the basic helix-loop-helix protein inhibitor of differentiation (Id)2 results in a similar defect. To investigate the role of Id2 in mammary epithelium, we performed structural and molecular analyses. Id2-null mammary epithelial cells were unable to form alveoli; the epithelial architecture was disorganized and dissimilar from early stages of alveologenesis in wild-type glands. The epithelial cells retained the ductal marker Na-K-Cl cotransporter (NKCC)1. Nuclear localization of Stat5a and down-regulation of NKCC1 was observed in some areas, indicating a limited response to pregnancy signals. The differentiation status of Id2-null tissue at term was further characterized with cDNA microarrays enriched in mammary specific sequences (mammochip). Some of the early differentiation markers for mammary epithelium were expressed in the Id2-null tissue, whereas genes that are expressed at later stages of pregnancy were not induced. From these results, we conclude that, in the absence of Id2, mammary epithelial development is arrested at an early stage of pregnancy.

scholarly journals NuMA-microtubule interactions are critical for spindle orientation and the morphogenesis of diverse epidermal structures

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Lindsey Seldin ◽  
Andrew Muroyama ◽  
Terry Lechler
Keyword(s):  
Cell Fate ◽  
Mitotic Spindle ◽  
Cell Types ◽  
Epidermal Differentiation ◽  
Spindle Orientation ◽  
Direct Function ◽  
Spindle Positioning ◽  
Adult Mice ◽  
Neonatal Lethality ◽  
The Matrix

Mitotic spindle orientation is used to generate cell fate diversity and drive proper tissue morphogenesis. A complex of NuMA and dynein/dynactin is required for robust spindle orientation in a number of cell types. Previous research proposed that cortical dynein/dynactin was sufficient to generate forces on astral microtubules (MTs) to orient the spindle, with NuMA acting as a passive tether. In this study, we demonstrate that dynein/dynactin is insufficient for spindle orientation establishment in keratinocytes and that NuMA’s MT-binding domain, which targets MT tips, is also required. Loss of NuMA-MT interactions in skin caused defects in spindle orientation and epidermal differentiation, leading to neonatal lethality. In addition, we show that NuMA-MT interactions are also required in adult mice for hair follicle morphogenesis and spindle orientation within the transit-amplifying cells of the matrix. Loss of spindle orientation in matrix cells results in defective differentiation of matrix-derived lineages. Our results reveal an additional and direct function of NuMA during mitotic spindle positioning, as well as a reiterative use of spindle orientation in the skin to build diverse structures.

Bovine mammary epithelial cells, initiators of innate immune responses to mastitis

2005 ◽  
Vol 45 (8) ◽  
pp. 757 ◽  
Author(s):  
C. Gray ◽  
Y. Strandberg ◽  
L. Donaldson ◽  
R. L. Tellam
Keyword(s):  
Immune Response ◽  
Mammary Gland ◽  
Epithelial Cells ◽  
Mammary Epithelial Cells ◽  
Vital Role ◽  
Mammary Epithelial ◽  
Innate Immune ◽  
Mammary Tissue ◽  
Effector Cells ◽  
Bovine Mammary Epithelial Cells

Innate immunity plays a vital role in the protection of the bovine mammary gland against mastitis. Until recently, the migration of effector cells such as neutrophils and monocytes into the mammary gland was thought to provide the only defence against invading pathogens. However, mammary epithelial cells may also play an important role in the immune response, contributing to the innate defence of the mammary tissue through secretion of antimicrobial peptides and attraction of circulating immune effector cells. This paper reviews the innate immune pathways in mammary epithelial cells and examines their role in the initiation of an innate immune response to Gram-positive and Gram-negative bacteria.

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